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US20140213605A1 - Methods for treating eye disorders using opioid receptor antagonists - Google Patents

Methods for treating eye disorders using opioid receptor antagonists Download PDF

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Publication number
US20140213605A1
US20140213605A1 US13/792,735 US201313792735A US2014213605A1 US 20140213605 A1 US20140213605 A1 US 20140213605A1 US 201313792735 A US201313792735 A US 201313792735A US 2014213605 A1 US2014213605 A1 US 2014213605A1
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United States
Prior art keywords
eye
disorders
corneal
opioid receptor
keratitis
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Abandoned
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US13/792,735
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English (en)
Inventor
Moshe Rogosnitzky
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REMEDEYE Inc
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REMEDEYE Inc
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Filing date
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Assigned to REMEDEYE INC. reassignment REMEDEYE INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ROGOSNITZKY, MOSHE
Publication of US20140213605A1 publication Critical patent/US20140213605A1/en
Priority to US14/636,211 priority Critical patent/US20150174122A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present invention relates to methods for treating eye disorders using opioid receptor antagonists.
  • dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which causes damage to the interpalpebral ocular surface associated with symptoms of ocular discomfort.
  • Chronic dryness leads to pain and irritation that is often debilitating to the subject, preventing the performance of normal daily activities such as reading and driving.
  • Dry eye is increasing in prevalence as the population ages. Approximately 4.9 million Americans 50 years old and older have dry eye. Many more have less severe symptoms notable only during contact with adverse contributing factors such as low humidity or contact lens wear, as well as the 21 million individuals with diabetes. The number of women affected with dry eye appears to exceed that of men.
  • ADDE aqueous tear-deficient dry eye
  • EEDE evaporative dry eye
  • ADDE refers mainly to a failure of sufficient tear secretion due to lacrimal dysfunction.
  • ADDE has two major subclasses, Sjogren's Syndrome dry eye (SSDE) and non-SS dry eye (such as in Graft-versus-Host Disease (GvHD) or in diabetes mellitus).
  • SSDE Sjogren's Syndrome dry eye
  • GvHD Graft-versus-Host Disease
  • EDE may be: (i) intrinsic, due to diseases affecting lid structures or dynamics, or (ii) extrinsic, in which ocular surface disease occurs due to some extrinsic exposure, such as topical drug preservatives, contact lens wear, pterygium, or vitamin A deficiency.
  • extrinsic in which ocular surface disease occurs due to some extrinsic exposure, such as topical drug preservatives, contact lens wear, pterygium, or vitamin A deficiency.
  • the boundary between these two categories is inevitably blurred.
  • the human cornea consists of epithelial cells, Bowman's membrane, corneal stroma, Descemet's membrane, and endothelial cells.
  • the cornea is normally avascular tissue, and receives nutrients from the aqueous humor in the anterior chamber of eye instead of blood vessels.
  • the cornea also lacks immunocytes. Therefore, the cornea is a very special tissue as compared to other tissues.
  • corneal ulcer usually refers to the medical condition in which the corneal stroma, or simply stroma (which mainly consists of collagen) is lysed and deleted by the activation and hypersecretion of collagenolytic enzyme.
  • the collagenolytic enzyme causing corneal ulcer, bacterial collagenase, and matrix metalloproteases (MMPs) are known to be involved in the ulcerative process.
  • corneal stromal cells When the cornea is infected with bacteria, bacterial collagenase is secreted, which directly degrades collagen in corneal stroma, and causes corneal ulcer. Simultaneously, microorganisms such as bacteria secrete other enzymes and toxins, and these factors become biological signals causing activation of corneal stromal cells (sometimes referred to as corneal fibroblasts). Other causes include viral, fungal, parasitic infection, or traumatic injury.
  • corneal epithelium cells are columnar at the basal section but become flatter toward the surface.
  • the epithelial cells are divided at the basal section, and gradually migrate upwards to finally be shed off and carried away by tears.
  • the corneal endothelial cells do not regenerate because they do not undergo cell division.
  • the delayed treatment or chronic state of corneal and conjunctival diseases such as dry eye, corneal ulcer, corneal erosion, pterygium, and keratitis damages the structures and functions of not only the epithelium, but also stroma and endothelium, and seriously impairs vision and barrier function.
  • the corneal/conjunctival diseases including a repeated erosion of the cornea and a prolonged corneal epithelial deficiency, are associated with such disorders.
  • the repairing process of the corneal/conjunctival epithelial disorders involves the coverage of the epithelial deficiency by the migration of corneal epithelial cells, followed by a subsequent cell division and differentiation, resulting in reconstitution of normal cornea and conjunctiva.
  • dry eyes also seriously impair vision and the barrier functions. This can occur when dry eyes result from, for example, (i) Sjogren's syndrome, (ii) Stevens Johnson syndrome, (iii) meibomian gland function insufficiency, (iv) VDT (visual display terminal) syndrome, (v) ophthalmological operations (e.g., cataract surgery, keratoplasty, refractive surgery); (vi) GvHD; (vii) keratoconjunctivitis sicca; and (viii) corneal disorders such as superficial punctate keratopathy (SPK), a fine, spot-like multiple epithelial deficiency occurring on the cornea epithelium (observed in, for example, drug-induced corneal epithelial disorders, neuroparalytic keratitis, diabetic keratopathy, and allergic conjunctivitis). Further, outbreaks of corneal epithelial damage such as superficial punctate keratopathy (SPK) among contact lens wearers have become a big problem in
  • eye disorder is specifically defined for use herein to include, but not be limited to, any ailment of Scleritis, Graft-versus-Host Disease (GvHD), keratitis, corneal ulcer, corneal abrasion, snow blindness, Thygeson's superficial punctuate keratopathy, corneal neovascularization, Fuch's dystrophy, keratoconus, keratoconjunctivitis sicca (dry eye), ulceris, corneal anesthesia, red eye, pink eye, keratomycosis, xeropthalmia, conjunctivitis, diabetic retinopathy, optic neuritis, orbital cellulitis, retinoblastoma, uveitis, pterygium, keratopathy, and Pingueculae.
  • GvHD Graft-versus-Host Disease
  • exemplary is used herein to refer to examples of embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case.
  • preferred is used herein to refer to an example out of an assortment of contemplated embodiments and/or implementations, and is not meant to necessarily convey a more-desirable use-case. Therefore, it is understood from the above that “exemplary” and “preferred” may be applied herein to multiple embodiments and/or implementations.
  • Opioids are drugs or endogenous substances that have actions similar to morphine. Endogenous or exogenous opioids exert their biological function in the body through binding to opioid receptors.
  • An opioid receptor antagonist is a chemical that competitively binds to opioid receptors, thus displacing either endogenous or exogenous opioids.
  • opioid antagonist drugs such as naloxone, naltrexone, and nalmefene are competitive antagonists that bind to the opioid receptors with higher affinity than agonists, but do not activate the receptors. This effectively blocks the receptor, preventing the body from responding to opioids and endorphins.
  • Naloxone, naltrexone, and nalmefene are pure opioid receptor antagonists, meaning that they exert an opioid-blocking effect in all opioid receptors.
  • Mixed or partial antagonists act as antagonists in certain receptors, and as agonists in others, thus giving a simultaneous, combined opioid and anti-opioid effect.
  • Embodiments of the present invention provide methods for treating eye disorders using opioid receptor antagonists, particularly, naltrexone, naloxone, and nalmefene.
  • opioid receptor antagonists particularly, naltrexone, naloxone, and nalmefene.
  • Naltrexone is a highly-specific opioid antagonist which has a high affinity for opioid receptor sites.
  • Naltrexone competitively displaces opioid agonists, such as opium, methadone, heroin, morphine, endogenous opioid peptides, beta-endorphin, and met-enkephalin, if one of these compounds is present.
  • the compound has few intrinsic actions besides its opioid-blocking properties.
  • Naltrexone does produce some pupillary constriction by an unknown mechanism, but does not cause any physiological tolerance or dependence. It is not known to block the effects of other classes of drugs besides opioids.
  • naltrexone appears to block some of the euphoriant actions of alcohol
  • Naltrexone is rapidly absorbed, with peak blood levels achieved about one hour after oral administration.
  • NTX has a relatively short plasma half-life of four hours. It is primarily metabolized in the liver to a metabolite, 6- ⁇ -naltrexol, which has a plasma half-life of about ten hours, and is also an opioid antagonist. Approximately 20% of the active metabolite is bound to plasma protein, and is distributed widely, with relatively high amounts in the brain, fat, spleen, heart, testes, kidney and urine. Naltrexone and 6- ⁇ -naltrexol undergo enterohepatic recycling, and are excreted primarily by the kidney. Less than 1% of naltrexone is excreted unchanged.
  • Naloxone is similar to naltrexone, having a similar function on opioid receptors; however, naloxone is very short-acting, as opposed to the long-acting effect of NTX.
  • Naloxone eye drops were reported to reverse the miosis in runners, having implications for an endogenous opiate test. Test results suggested that exercise generated endogenous opiates which cause pupillary miosis, and that applying topical naloxone to one eye can block this exercise pupillary effect resulting in ipsilateral mydriasis.
  • Nalmefene is an opiate derivative similar both in structure and activity to the opioid antagonist naltrexone. Advantages of nalmefene relative to NTX include longer half-life, greater oral bioavailability, and no observed dose-dependent liver toxicity.
  • Vigamox is the brand name for moxifloxacin (MXF), a fourth-generation synthetic fluoroquinolone antibacterial agent (methoxyfluoroquinolone). MXF also goes by the brand name Avelox. In a study conducted by Choi et al. ( Antimicrob Agents Chemother., 2003 December; 47(12): 3704-3707), MXF was shown to inhibit the production of inflammatory proteins such as tumor necrosis factor alpha (TNF- ⁇ ) and/or interleukin-6 (IL-6), and to reduce the population of cells positive for CD-14 and TNF- ⁇ and for CD-14 and IL-6 among the LPS- or LTA-stimulated, human peripheral blood mononuclear cells (PBMCs).
  • TNF- ⁇ tumor necrosis factor alpha
  • IL-6 interleukin-6
  • pro-inflammatory factor such as IL-8, IL-6, ERK1/2, JNK, and NF- ⁇ B in human lung epithelial cells.
  • MXF modifies corneal fibroblast-to-myofibroblast differentiation. MXF retarded HCF-containing gel contractility and ⁇ -SMA filament formation following TGF- ⁇ 1 stimulation, and blocked expression of Smad2, phospho-Smad2-Ser467, and TGFBR1 under TGF- ⁇ 1 incubation, as well as enhanced Smad7 expression in TGF- ⁇ 1-incubated HCFs, but did not interfere with TGF- ⁇ 1-triggered Smad2 nuclear translocation or Smad4 expression.
  • MXF is an active chemical agent with properties and interactions that go well beyond typical antimicrobial effects.
  • MXF or its class of antibiotics
  • topical MXF use poses at least a comparable risk.
  • prolonged use of MXF for eye disorders poses an additional risk of contracting fungal infections.
  • indiscriminate use of antibiotics in general is the main known cause of antibiotic resistance.
  • 31 CFR ⁇ 300.50 of the United States Food and Drug Administration's policy regarding fixed combination dosage form prescription drugs for humans, states that two or more drugs may be combined in a single dosage form when (i) each component makes a contribution to the claimed effects, and (ii) the dosage of each component (amount, frequency, duration) is such that the combination is safe and effective for a significant patient population requiring such concurrent therapy as defined in the labeling for the drug.
  • the European Medicines Agency has similar guidelines to the FDA, stating that the development of fixed-combination medicinal products will reflect the intended use and the intended indication.
  • the proposed combination should always be based on valid therapeutic principles.
  • it is necessary to assess the potential advantages (e.g., product rapidly effective, higher efficacy or equal efficacy, and better safety) in the clinical situation against possible disadvantages (e.g., cumulative toxicity) for each fixed combination product and for each dose of the fixed combination product.
  • opioid receptor antagonists were found to be effective in treating ocular medical conditions when applied topically in physiological saline formulations.
  • topical application of opioid receptor antagonists may serve to treat dry eye caused by, for example, Graft-versus-Host Disease (GvHD), diabetes, allergic conjunctivitis, contact lens-related dry eye, and Sjorgen's syndrome.
  • GvHD Graft-versus-Host Disease
  • diabetes for example, diabetes, allergic conjunctivitis, contact lens-related dry eye, and Sjorgen's syndrome.
  • topical opioid receptor antagonists may also be used to treat corneal ulcers resulting from, for example: viral infection, bacterial infection, fungal infection, injury resulting from wearing contact lenses, traumatic injury, and parasite infection.
  • topical opioid receptor antagonists may also be used for the treatment of pterygium, corneal anesthesia, and corneal neovascularization.
  • a method for treating eye disorders using opioid receptor antagonists including the step of: (a) administering an effective amount of a topically-administered opioid receptor antagonist in the absence of moxifloxacin.
  • the topically-administered opioid receptor antagonist is formulated as a solution.
  • the topically-administered opioid receptor antagonist is at least one agent selected from the group consisting of: naltrexone, naloxone, nalmefene, and a pharmaceutically-acceptable salt thereof.
  • the effective amount corresponds to a concentration of at least about 10 ⁇ 7 molarity.
  • the effective amount is based on a treatment administration of at least once every other day.
  • the present invention relates to methods for treating eye disorders using opioid receptor antagonists.
  • the aspects, uses, and advantages for such methods and treatment indications, according to the present invention may be better understood with reference to the accompanying description.
  • Naltrexone eye drops were prepared as follows. 1 mg naltrexone hydrochloride USP was weighed and diluted in 265 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 3.77 mcg of naltrexone per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • Naltrexone eye drops were prepared as follows. 1 mg naltrexone hydrochloride USP was weighed and diluted in 132.5 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 7.54 mcg of naltrexone per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • Naloxone eye drops were prepared as follows. 0.5 mg naloxone hydrochloride USP was weighed and diluted in 265 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 1.886 mcg of naloxone per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • Naloxone eye drops were prepared as follows. 0.5 mg naloxone hydrochloride USP was weighed and diluted in 132.5 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 3.77 mcg of naloxone per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • Nalmefene eye drops were prepared as follows. 1 mg nalmefene hydrochloride USP was weighed and diluted in 265 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 3.77 mcg of nalmefene per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • Nalmefene eye drops were prepared as follows. 1 mg nalmefene hydrochloride USP was weighed and diluted in 132.5 ml saline (0.9% w/v sodium chloride in sterile water). This gave a solution containing 7.54 mcg of nalmefene per ml. Using a dropper, one drop (equivalent to approximately 0.05 ml) was applied to the eye.
  • a human male suffering from diabetes-related dry eye was treated with one drop of Formulation B (naltrexone) bilaterally twice daily. Relief from the dry-eye symptoms was attained within half an hour. The patient required subsequent application twice daily. After 10 days of use, redness in the eye (or pink eye) disappeared.
  • a human female suffering from diabetes-related dry eye was treated with one drop of Formulation B (naltrexone) bilaterally once every other day. Relief from the dry-eye symptoms was attained within half an hour. The patient required subsequent application once every other day. After 10 days of use, redness in the eye (or pink eye) disappeared.
  • a human male suffering from a viral eye infection with corneal abrasion i.e., the onset of a corneal ulcer
  • corneal abrasion i.e., the onset of a corneal ulcer
  • Formulation A naltrexone
  • Exudation ceased within 6 hours.
  • the patient required subsequent application twice daily. After 2 days of use, redness in the eye (or pink eye) disappeared, and the eye was complete healed within 5 days.
  • Formulation B naltrexone
  • a human male suffering from a corneal ulcer in one eye was treated with one drop of Formulation A (naltrexone) twice daily. Relief from pain and irritation was attained within 36 hours. The patient required subsequent application twice daily. After 7 days of use, the ulcer had healed completely.
  • Formulation A naltrexone
  • Formulation D naloxone
  • a human female suffering from a corneal ulcer in one eye was treated with one drop of Formulation E (nalmefene) twice daily. Relief from pain and irritation was attained within 24 hours. The patient required subsequent application twice daily. After 7 days of use, the ulcer had healed completely.

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US13/792,735 2013-01-27 2013-03-11 Methods for treating eye disorders using opioid receptor antagonists Abandoned US20140213605A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129145A2 (fr) * 2009-04-28 2010-11-11 Zagon Ian S Procédés et compositions pour traiter l'œil sec

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* Cited by examiner, † Cited by third party
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US20050009836A1 (en) * 2003-06-26 2005-01-13 Laskar Paul A. Ophthalmic composition containing quinolones and method of use
ES2475199T3 (es) * 2008-09-16 2014-07-10 Imuneks Farma Ila� Sanayi Ve Ticaret A.S. Uso de antagonistas opioides para la preparación de un medicamento en el tratamiento de enfermedades degenerativas de la retina

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010129145A2 (fr) * 2009-04-28 2010-11-11 Zagon Ian S Procédés et compositions pour traiter l'œil sec

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
Fraunfelder et al ("The Role of Medications in Causing Dry Eye," Journal of Ophthalmology, 2012; 2012:1-8) *
Michel et al ("Binding of a New Opiate Antagonist, Nalmefene, to Rat Brain Membranes." Meth and Find Exptl Clin Pharmacol, 1985; 7(4):175-177. *
Sullivan et al (Investigative Ophthalmology & Visual Science, 2010; 51(12):6125-6130 *
Vigamox® Product Monograph (Alcon Canada Inc, Control: 081217; Date of Revision: January 9, 2012) *

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US20150174122A1 (en) 2015-06-25

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